C17-heteroaryl derivatives of oleanolic acid and methods of use thereof

ABSTRACT

Disclosed herein are novel C17-heteroaryl derivatives of oleanolic acid, including those of the formula: 
                         
wherein the variables are defined herein. Also provided are pharmaceutical compositions, kits and articles of manufacture comprising such compounds. Methods and intermediates useful for making the compounds, and methods of using the compounds, for example, as antioxidant inflammation modulators, and compositions thereof are also provided.

This application is a divisional application of U.S. patent applicationSer. No. 15/349,086, filed Nov. 11, 2016, which is a divisionalapplication of U.S. patent application Ser. No. 14/566,827, filed Dec.11, 2014, now U.S. Pat. No. 9,512,094, issued on Dec. 6, 2016, which isa continuation-in-part application of U.S. patent application Ser. No.14/022,843, filed on Sep. 10, 2013, abandoned, which claims the benefitof U.S. Provisional Patent Application No. 61/699,199, filed on Sep. 10,2012. The entire contents of the above-referenced disclosures arespecifically incorporated herein by reference.

The sequence listing that is contained in the file named“REATP0076USCP1D2_ST25.txt”, which is ˜1 KB (as measured in MicrosoftWindows®) and was created on Jan. 2, 2018, is filed herewith byelectronic submission and is incorporated by reference herein.

BACKGROUND OF THE INVENTION

I. Field of the Invention

The present invention relates generally to the fields of biology andmedicine. More particularly, it concerns compounds, compositions andmethods for the treatment and prevention of diseases such as thoseassociated with oxidative stress and inflammation.

II. Description of Related Art

The anti-inflammatory and anti-proliferative activity of the naturallyoccurring triterpenoid, oleanolic acid, has been improved by chemicalmodifications. For example,2-cyano-3,12-diooxooleana-1,9(11)-dien-28-oic acid (CDDO) and relatedcompounds have been developed (Honda et al., 1997; Honda et al., 1998;Honda et al., 1999; Honda et al., 2000a; Honda et al., 2000b; Honda, etal., 2002; Suh et al. 1998; Suh et al., 1999; Place et al., 2003; Libyet al., 2005; and U.S. Pat. Nos. 8,129,429; 7,915,402; 8,124,799;8,071,632; 8,338,618; and 7,943,778). The methyl ester, bardoxolonemethyl (CDDO-Me), has been evaluated clinically for the treatment ofcancer and chronic kidney disease (Pergola et al., 2011; Hong et al.,2012).

Synthetic triterpenoid analogs of oleanolic acid have also been shown tobe inhibitors of cellular inflammatory processes, such as the inductionby IFN-γ of inducible nitric oxide synthase (iNOS) and of COX-2 in mousemacrophages. See Honda et al. (2000a); Honda et al. (2000b), and Hondaet al. (2002). Synthetic derivatives of another triterpenoid, betulinicacid, have also been shown to inhibit cellular inflammatory processes,although these compounds have been less extensively characterized (Hondaet al., 2006). The pharmacology of these synthetic triterpenoidmolecules is complex. Compounds derived from oleanolic acid have beenshown to affect the function of multiple protein targets and therebymodulate the activity of several important cellular signaling pathwaysrelated to oxidative stress, cell cycle control, and inflammation (e.g.,Dinkova-Kostova et al., 2005; Ahmad et al., 2006; Ahmad et al., 2008;Liby et al., 2007a). Derivatives of betulinic acid, though they haveshown comparable anti-inflammatory properties, also appear to havesignificant differences in their pharmacology compared to OA-derivedcompounds (Liby et al., 2007b). Given that the biological activityprofiles of known triterpenoid derivatives vary, and in view of the widevariety of diseases that may be treated or prevented with compoundshaving potent antioxidant and anti-inflammatory effects, and the highdegree of unmet medical need represented within this variety ofdiseases, it is desirable to synthesize new compounds with diversestructures that may have improved biological activity profiles for thetreatment of one or more indications.

SUMMARY OF THE INVENTION

The present disclosure provides novel synthetic triterpenoid derivativeswith anti-inflammatory and/or antioxidant properties, pharmaceuticalcompositions, and methods for their manufacture, and methods for theiruse.

In one aspect, there are provided compounds of the formula:

wherein:

-   -   n is 0-3;    -   Ar is heteroarenediyl _((C≤8)) or a substituted version thereof;        and    -   Y is:        -   hydrogen, hydroxy, halo, amino, or cyano or —NCO; or        -   alkyl_((C≤8)), alkenyl_((C≤8)), alkynyl_((C≤8)),            aryl_((C≤12)), aralkyl_((C≤12)), heteroaryl_((C≤8)),            heterocycloalkyl_((C≤12)), acyl_((C≤12)), alkoxy_((C≤8)),            aryloxy_((C≤12)), acyl-oxy_((C≤8)), alkylamino_((C≤8)),            dialkylamino_((C≤8)), arylamino_((C≤8)),            aralkyl-amino_((C≤8)), alkylthio_((C≤8)), acylthio_((C≤8)),            alkylsulfonylamino_((C≤8)), or substituted versions of any            of these groups;            or a pharmaceutically acceptable salt thereof.

In some embodiments, Y is —H. In some embodiments, Y is alkyl_((C≤4)),for example, methyl, n-propyl, isopropyl or cyclopropyl. In someembodiments, Y is substituted alkyl_((C≤4)), for example, methoxymethyl.

In some embodiments, Ar is

In some embodiments, n=0. In other embodiments, n=1.

In some embodiments, the compound is selected from the group consistingof:

or a pharmaceutically acceptable salt of any of the above formulas.

In another aspect, there are provided compounds of the formula:

wherein:

-   -   n is 0-3;    -   Ar is heteroarenediyl_((C≤8)) or a substituted version thereof;    -   Y is:        -   hydrogen, hydroxy, halo, amino, or cyano or —NCO; or        -   alkyl_((C≤8)), alkenyl_((C≤8)), alkynyl_((C≤8)),            aryl_((C≤12)), aralkyl_((C≤12)), heteroaryl_((C≤8)),            heterocycloalkyl_((C≤12)), acyl_((C≤12)), alkoxy_((C≤8)),            aryloxy_((C≤12)), acyloxy_((C≤8)), alkylamino_((C≤8)),            dialkylamino_((C≤8)), arylamino_((C≤8)),            aralkylamino_((C≤8)), alkylthio_((C≤8)), acylthio_((C≤8)),            alkylsulfonylamino_((C≤8)), or substituted versions of any            of these groups; and    -   X is —CN, halo, —CF₃, or —C(O)R_(a), wherein R_(a) is —OH,        alkoxy_((C1-4)), —NH₂, alkylamino_((C1-4)), or        —NH—S(O)₂-alkyl_((C1-4));        or a pharmaceutically acceptable salt thereof.

In some aspects, there are provided pharmaceutical compositionscomprising one or more of the above compounds and an excipient. In otheraspects there are provided methods of treating and/or preventing adisease or a disorder in patients in need thereof, comprisingadministering to such patients one or more of the above compounds in anamount sufficient to treat and/or prevent the disease or disorder.

Other objects, features and advantages of the present disclosure willbecome apparent from the following detailed description. It should beunderstood, however, that the detailed description and the specificexamples, while indicating specific embodiments of the invention, aregiven by way of illustration only, since various changes andmodifications within the spirit and scope of the invention will becomeapparent to those skilled in the art from this detailed description.Note that simply because a particular compound is ascribed to oneparticular generic formula doesn't mean that it cannot also belong toanother generic formula.

DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

Disclosed herein are new compounds and compositions with antioxidantand/or anti-inflammatory properties, methods for their manufacture, andmethods for their use, including for the treatment and/or prevention ofdisease.

I. Definitions

When used in the context of a chemical group: “hydrogen” means —H;“hydroxy” means —OH; “oxo” means ═O; “carbonyl” means —C(═O)—; “carboxy”means —C(═O)OH (also written as —COOH or —CO₂H); “halo” meansindependently —F, —Cl, —Br or —I; “amino” means —NH₂; “hydroxyamino”means —NHOH; “nitro” means —NO₂; imino means ═NH; “cyano” means —CN;“isocyanate” means —N═C═O; “azido” means —N₃; in a monovalent context“phosphate” means —OP(O)(OH)₂ or a deprotonated form thereof; in adivalent context “phosphate” means —OP(O)(OH)O— or a deprotonated formthereof; “mercapto” means —SH; and “thio” means ═S; “sulfonyl” means—S(O)₂—; and “sulfinyl” means —S(O)—.

In the context of chemical formulas, the symbol “—” means a single bond,“=” means a double bond, and “≡” means triple bond. The symbol “

” represents an optional bond, which if present is either single ordouble. The symbol “

” represents a single bond or a double bond. Thus, for example, theformula

includes

And it is understood that no one such ring atom forms part of more thanone double bond. Furthermore, it is noted that the covalent bond symbol“—”, when connecting one or two stereogenic atoms, does not indicate anypreferred stereochemistry. Instead, it cover all stereoisomers as wellas mixtures thereof. The symbol “

”, when drawn perpendicularly across a bond (e.g.,

for methyl) indicates a point of attachment of the group. It is notedthat the point of attachment is typically only identified in this mannerfor larger groups in order to assist the reader in unambiguouslyidentifying a point of attachment. The symbol “

” means a single bond where the group attached to the thick end of thewedge is “out of the page.” The symbol “

” means a single bond where the group attached to the thick end of thewedge is “into the page”. The symbol “

” means a single bond where the geometry around a double bond (e.g.,either E or Z) is undefined. Both options, as well as combinationsthereof are therefore intended. The bond orders described above are notlimiting when one of the atoms connected by the bond is a metal atom(M). In such cases, it is understood that the actual bonding maycomprise significant multiple bonding and/or ionic character. Therefore,unless indicated otherwise, the formulas M-C, M=C,

each refers to a bond of any and type and order between a metal atom anda carbon atom. Any undefined valency on an atom of a structure shown inthis application implicitly represents a hydrogen atom bonded to thatatom. A bold dot on a carbon atom indicates that the hydrogen attachedto that carbon is oriented out of the plane of the paper.

When a group “R” is depicted as a “floating group” on a ring system, forexample, in the formula:

then R may replace any hydrogen atom attached to any of the ring atoms,including a depicted, implied, or expressly defined hydrogen, so long asa stable structure is formed. When a group “R” is depicted as a“floating group” on a fused ring system, as for example in the formula:

then R may replace any hydrogen attached to any of the ring atoms ofeither of the fused rings unless specified otherwise. Replaceablehydrogens include depicted hydrogens (e.g., the hydrogen attached to thenitrogen in the formula above), implied hydrogens (e.g., a hydrogen ofthe formula above that is not shown but understood to be present),expressly defined hydrogens, and optional hydrogens whose presencedepends on the identity of a ring atom (e.g., a hydrogen attached togroup X, when X equals —CH—), so long as a stable structure is formed.In the example depicted, R may reside on either the 5-membered or the6-membered ring of the fused ring system. In the formula above, thesubscript letter “y” immediately following the group “R” enclosed inparentheses, represents a numeric variable. Unless specified otherwise,this variable can be 0, 1, 2, or any integer greater than 2, onlylimited by the maximum number of replaceable hydrogen atoms of the ringor ring system.

For the groups and classes below, the following parenthetical subscriptsfurther define the group/class as follows: “(Cn)” defines the exactnumber (n) of carbon atoms in the group/class. “(C≤n)” defines themaximum number (n) of carbon atoms that can be in the group/class, withthe minimum number as small as possible for the group in question, e.g.,it is understood that the minimum number of carbon atoms in the group“alkenyl_((C≤8))” or the class “alkene_((C≤8))” is two. For example,“alkoxy_((C≤10))” designates those alkoxy groups having from 1 to 10carbon atoms. (Cn-n′) defines both the minimum (n) and maximum number(n′) of carbon atoms in the group. Similarly, “alkyl_((C2-10))”designates those alkyl groups having from 2 to 10 carbon atoms.

The term “saturated” as used herein means the compound or group somodified has no carbon-carbon double and no carbon-carbon triple bonds,except as noted below. In the case of substituted versions of saturatedgroups, one or more carbon oxygen double bond or a carbon nitrogendouble bond may be present. And when such a bond is present, thencarbon-carbon double bonds that may occur as part of keto-enoltautomerism or imine/enamine tautomerism are not precluded.

The term “aliphatic” when used without the “substituted” modifiersignifies that the compound/group so modified is an acyclic or cyclic,but non-aromatic hydrocarbon compound or group. In aliphaticcompounds/groups, the carbon atoms can be joined together in straightchains, branched chains, or non-aromatic rings (alicyclic). Aliphaticcompounds/groups can be saturated, that is joined by single bonds(alkanes/alkyl), or unsaturated, with one or more double bonds(alkenes/alkenyl) or with one or more triple bonds (alkynes/alkynyl).

The term “alkyl” when used without the “substituted” modifier refers toa monovalent saturated aliphatic group with a carbon atom as the pointof attachment, a linear or branched, cyclo, cyclic or acyclic structure,and no atoms other than carbon and hydrogen. Thus, as used hereincycloalkyl is a subset of alkyl, with the carbon atom that forms thepoint of attachment also being a member of one or more non-aromatic ringstructures wherein the cycloalkyl group consists of no atoms other thancarbon and hydrogen. As used herein, the term does not preclude thepresence of one or more alkyl groups (carbon number limitationpermitting) attached to the ring or ring system. The groups —CH₃ (Me),—CH₂CH₃ (Et), —CH₂CH₂CH₃ (n-Pr or propyl), —CH(CH₃)₂ (i-Pr, ^(i)Pr orisopropyl), —CH(CH₂)₂ (cyclopropyl), —CH₂CH₂CH₂CH₃ (n-Bu),—CH(CH₃)CH₂CH₃ (sec-butyl), —CH₂CH(CH₃)₂ (isobutyl), —C(CH₃)₃(tert-butyl, t-butyl, t-Bu or ^(t)Bu), —CH₂C(CH₃)₃ (neo-pentyl),cyclobutyl, cyclopentyl, cyclohexyl, and cyclohexylmethyl arenon-limiting examples of alkyl groups. The term “alkanediyl” when usedwithout the “substituted” modifier refers to a divalent saturatedaliphatic group, with one or two saturated carbon atom(s) as thepoint(s) of attachment, a linear or branched, cyclo, cyclic or acyclicstructure, no carbon-carbon double or triple bonds, and no atoms otherthan carbon and hydrogen. The groups, —CH₂— (methylene), —CH₂CH₂—,—CH₂C(CH₃)₂CH₂—, —CH₂CH₂CH₂—, and

are non-limiting examples of alkanediyl groups. The term “alkylidene”when used without the “substituted” modifier refers to the divalentgroup ═CRR′ in which R and R′ are independently hydrogen, alkyl, or Rand R′ are taken together to represent an alkanediyl having at least twocarbon atoms. Non-limiting examples of alkylidene groups include: ═CH₂,═CH(CH₂CH₃), and ═C(CH₃)₂. An “alkane” refers to the compound H—R,wherein R is alkyl as this term is defined above. When any of theseterms is used with the “substituted” modifier one or more hydrogen atomhas been independently replaced by —OH, —F, —Cl, —Br, —I, —NH₂, —NO₂,—CO₂H, —CO₂CH₃, —CN, —SH, —OCH₃, —OCH₂CH₃, —C(O)CH₃, —NHCH₃, —NHCH₂CH₃,—N(CH₃)₂, —C(O)NH₂, —OC(O)CH₃, or —S(O)₂NH₂. The following groups arenon-limiting examples of substituted alkyl groups: —CH₂OH, —CH₂Cl, —CF₃,—CH₂CN, —CH₂C(O)OH, —CH₂C(O)OCH₃, —CH₂C(O)NH₂, —CH₂C(O)CH₃, —CH₂OCH₃,—CH₂OC(O)CH₃, —CH₂NH₂, —CH₂N(CH₃)₂, and —CH₂CH₂Cl. The term “haloalkyl”is a subset of substituted alkyl, in which one or more hydrogen atomshas been substituted with a halo group and no other atoms aside fromcarbon, hydrogen and halogen are present. The group, —CH₂Cl is anon-limiting example of a haloalkyl. The term “fluoroalkyl” is a subsetof substituted alkyl, in which one or more hydrogen has been substitutedwith a fluoro group and no other atoms aside from carbon, hydrogen andfluorine are present. The groups, —CH₂F, —CF₃, and —CH₂CF₃ arenon-limiting examples of fluoroalkyl groups.

The term “alkenyl” when used without the “substituted” modifier refersto an monovalent unsaturated aliphatic group with a carbon atom as thepoint of attachment, a linear or branched, cyclo, cyclic or acyclicstructure, at least one nonaromatic carbon-carbon double bond, nocarbon-carbon triple bonds, and no atoms other than carbon and hydrogen.Non-limiting examples of alkenyl groups include: —CH═CH₂ (vinyl),—CH═CHCH₃, —CH═CHCH₂CH₃, —CH₂CH═CH₂ (allyl), —CH₂CH═CHCH₃, and—CH═CHCH═CH₂. The term “alkenediyl” when used without the “substituted”modifier refers to a divalent unsaturated aliphatic group, with twocarbon atoms as points of attachment, a linear or branched, cyclo,cyclic or acyclic structure, at least one nonaromatic carbon-carbondouble bond, no carbon-carbon triple bonds, and no atoms other thancarbon and hydrogen. The groups, —CH═CH—, —CH═C(CH₃)CH₂—, —CH═CHCH₂—,and

are non-limiting examples of alkenediyl groups. It is noted that whilethe alkenediyl group is aliphatic, once connected at both ends, thisgroup is not precluded from forming part of an aromatic structure. Theterms “alkene” or “olefin” are synonymous and refer to a compound havingthe formula H—R, wherein R is alkenyl as this term is defined above. A“terminal alkene” refers to an alkene having just one carbon-carbondouble bond, wherein that bond forms a vinyl group at one end of themolecule. When any of these terms are used with the “substituted”modifier one or more hydrogen atom has been independently replaced by—OH, —F, —Cl, —Br, —I, —NH₂, —NO₂, —CO₂H, —CO₂CH₃, —CN, —SH, —OCH₃,—OCH₂CH₃, —C(O)CH₃, —NHCH₃, —NHCH₂CH₃, —N(CH₃)₂, —C(O)NH₂, —OC(O)CH₃, or—S(O)₂NH₂. The groups, —CH═CHF, —CH═CHCl and —CH═CHBr, are non-limitingexamples of substituted alkenyl groups.

The term “alkynyl” when used without the “substituted” modifier refersto an monovalent unsaturated aliphatic group with a carbon atom as thepoint of attachment, a linear or branched, cyclo, cyclic or acyclicstructure, at least one carbon-carbon triple bond, and no atoms otherthan carbon and hydrogen. As used herein, the term alkynyl does notpreclude the presence of one or more non-aromatic carbon-carbon doublebonds. The groups, —C≡CH, —C≡CCH₃, and —CH₂C≡CCH₃, are non-limitingexamples of alkynyl groups. An “alkyne” refers to the compound H—R,wherein R is alkynyl. When any of these terms are used with the“substituted” modifier one or more hydrogen atom has been independentlyreplaced by —OH, —F, —Cl, —Br, —I, —NH₂, —NO₂, —CO₂H, —CO₂CH₃, —CN, —SH,—OCH₃, —OCH₂CH₃, —C(O)CH₃, —NHCH₃, —NHCH₂CH₃, —N(CH₃)₂, —C(O)NH₂,—OC(O)CH₃, or —S(O)₂NH₂.

The term “aryl” when used without the “substituted” modifier refers to amonovalent unsaturated aromatic group with an aromatic carbon atom asthe point of attachment, said carbon atom forming part of a one or moresix-membered aromatic ring structure, wherein the ring atoms are allcarbon, and wherein the group consists of no atoms other than carbon andhydrogen. If more than one ring is present, the rings may be fused orunfused. As used herein, the term does not preclude the presence of oneor more alkyl or aralkyl groups (carbon number limitation permitting)attached to the first aromatic ring or any additional aromatic ringpresent. Non-limiting examples of aryl groups include phenyl (Ph),methylphenyl, (dimethyl)phenyl, —C₆H₄CH₂CH₃ (ethylphenyl), naphthyl, anda monovalent group derived from biphenyl. The term “arenediyl” when usedwithout the “substituted” modifier refers to a divalent aromatic groupwith two aromatic carbon atoms as points of attachment, said carbonatoms forming part of one or more six-membered aromatic ringstructure(s) wherein the ring atoms are all carbon, and wherein themonovalent group consists of no atoms other than carbon and hydrogen. Asused herein, the term does not preclude the presence of one or morealkyl, aryl or aralkyl groups (carbon number limitation permitting)attached to the first aromatic ring or any additional aromatic ringpresent. If more than one ring is present, the rings may be fused orunfused. Unfused rings may be connected via one or more of thefollowing: a covalent bond, alkanediyl, or alkenediyl groups (carbonnumber limitation permitting). Non-limiting examples of arenediyl groupsinclude:

An “arene” refers to the compound H—R, wherein R is aryl as that term isdefined above. Benzene and toluene are non-limiting examples of arenes.When any of these terms are used with the “substituted” modifier one ormore hydrogen atom has been independently replaced by —OH, —F, —Cl, —Br,—I, —NH₂, —NO₂, —CO₂H, —CO₂CH₃, —CN, —SH, —OCH₃, —OCH₂CH₃, —C(O)CH₃,—NHCH₃, —NHCH₂CH₃, —N(CH₃)₂, —C(O)NH₂, —OC(O)CH₃, or —S(O)₂NH₂.

The term “aralkyl” when used without the “substituted” modifier refersto the monovalent group -alkanediyl-aryl, in which the terms alkanediyland aryl are each used in a manner consistent with the definitionsprovided above. Non-limiting examples of aralkyls are: phenylmethyl(benzyl, Bn) and 2-phenyl-ethyl. When the term aralkyl is used with the“substituted” modifier one or more hydrogen atom from the alkanediyland/or the aryl group has been independently replaced by —OH, —F, —Cl,—Br, —I, —NH₂, —NO₂, —CO₂H, —CO₂CH₃, —CN, —SH, —OCH₃, —OCH₂CH₃,—C(O)CH₃, —NHCH₃, —NHCH₂CH₃, —N(CH₃)₂, —C(O)NH₂, —OC(O)CH₃, or—S(O)₂NH₂. Non-limiting examples of substituted aralkyls are:(3-chlorophenyl)-methyl, and 2-chloro-2-phenyl-eth-1-yl.

The term “heteroaryl” when used without the “substituted” modifierrefers to a monovalent aromatic group with an aromatic carbon atom ornitrogen atom as the point of attachment, said carbon atom or nitrogenatom forming part of one or more aromatic ring structures wherein atleast one of the ring atoms is nitrogen, oxygen or sulfur, and whereinthe heteroaryl group consists of no atoms other than carbon, hydrogen,aromatic nitrogen, aromatic oxygen and aromatic sulfur. If more than onering is present, the rings may be fused or unfused. As used herein, theterm does not preclude the presence of one or more alkyl, aryl, and/oraralkyl groups (carbon number limitation permitting) attached to thearomatic ring or aromatic ring system. Non-limiting examples ofheteroaryl groups include furanyl, imidazolyl, indolyl, indazolyl (Im),isoxazolyl, methylpyridinyl, oxazolyl, phenylpyridinyl, pyridinyl,pyrrolyl, pyrimidinyl, pyrazinyl, quinolyl, quinazolyl, quinoxalinyl,triazinyl, tetrazolyl, thiazolyl, thienyl, and triazolyl. The term“N-heteroaryl” refers to a heteroaryl group with a nitrogen atom as thepoint of attachment. The term “heteroarenediyl” when used without the“substituted” modifier refers to an divalent aromatic group, with twoaromatic carbon atoms, two aromatic nitrogen atoms, or one aromaticcarbon atom and one aromatic nitrogen atom as the two points ofattachment, said atoms forming part of one or more aromatic ringstructure(s) wherein at least one of the ring atoms is nitrogen, oxygenor sulfur, and wherein the divalent group consists of no atoms otherthan carbon, hydrogen, aromatic nitrogen, aromatic oxygen and aromaticsulfur. If more than one ring is present, the rings may be fused orunfused. Unfused rings may be connected via one or more of thefollowing: a covalent bond, alkanediyl, or alkenediyl groups (carbonnumber limitation permitting). As used herein, the term does notpreclude the presence of one or more alkyl, aryl, and/or aralkyl groups(carbon number limitation permitting) attached to the aromatic ring oraromatic ring system. Non-limiting examples of heteroarenediyl groupsinclude:

A “heteroarene” refers to the compound H—R, wherein R is heteroaryl.Pyridine and quinoline are non-limiting examples of heteroarenes. Whenthese terms are used with the “substituted” modifier one or morehydrogen atom has been independently replaced by —OH, —F, —Cl, —Br, —I,—NH₂, —NO₂, —CO₂H, —CO₂CH₃, —CN, —SH, —OCH₃, —OCH₂CH₃, —C(O)CH₃, —NHCH₃,—NHCH₂CH₃, —N(CH₃)₂, —C(O)NH₂, —OC(O)CH₃, or —S(O)₂NH₂.

The term “heterocycloalkyl” when used without the “substituted” modifierrefers to a monovalent non-aromatic group with a carbon atom or nitrogenatom as the point of attachment, said carbon atom or nitrogen atomforming part of one or more non-aromatic ring structures wherein atleast one of the ring atoms is nitrogen, oxygen or sulfur, and whereinthe heterocycloalkyl group consists of no atoms other than carbon,hydrogen, nitrogen, oxygen and sulfur. If more than one ring is present,the rings may be fused or unfused. As used herein, the term does notpreclude the presence of one or more alkyl groups (carbon numberlimitation permitting) attached to the ring or ring system. Also, theterm does not preclude the presence of one or more double bonds in thering or ring system, provided that the resulting group remainsnon-aromatic. Non-limiting examples of heterocycloalkyl groups includeaziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl,morpholinyl, thiomorpholinyl, tetrahydrofuranyl, tetrahydrothiofuranyl,tetrahydropyranyl, pyranyl, oxiranyl, and oxetanyl. The term“N-heterocycloalkyl” refers to a heterocycloalkyl group with a nitrogenatom as the point of attachment. The term “heterocycloalkanediyl” whenused without the “substituted” modifier refers to an divalent cyclicgroup, with two carbon atoms, two nitrogen atoms, or one carbon atom andone nitrogen atom as the two points of attachment, said atoms formingpart of one or more ring structure(s) wherein at least one of the ringatoms is nitrogen, oxygen or sulfur, and wherein the divalent groupconsists of no atoms other than carbon, hydrogen, nitrogen, oxygen andsulfur. If more than one ring is present, the rings may be fused orunfused. Unfused rings may be connected via one or more of thefollowing: a covalent bond, alkanediyl, or alkenediyl groups (carbonnumber limitation permitting). As used herein, the term does notpreclude the presence of one or more alkyl groups (carbon numberlimitation permitting) attached to the ring or ring system. Also, theterm does not preclude the presence of one or more double bonds in thering or ring system, provided that the resulting group remainsnon-aromatic. Non-limiting examples of heterocycloalkanediyl groupsinclude:

When these terms are used with the “substituted” modifier one or morehydrogen atom has been independently replaced by —OH, —F, —Cl, —Br, —I,—NH₂, —NO₂, —CO₂H, —CO₂CH₃, —CN, —SH, —OCH₃, —OCH₂CH₃, —C(O)CH₃, —NHCH₃,—NHCH₂CH₃, —N(CH₃)₂, —C(O)NH₂, —OC(O)CH₃, —S(O)₂NH₂, or —C(O)OC(CH₃)₃(tert-butyloxycarbonyl, BOC).

The term “acyl” when used without the “substituted” modifier refers tothe group —C(O)R, in which R is a hydrogen, alkyl, aryl, aralkyl orheteroaryl, as those terms are defined above. The groups, —CHO, —C(O)CH₃(acetyl, Ac), —C(O)CH₂CH₃, —C(O)CH₂CH₂CH₃, —C(O)CH(CH₃)₂, —C(O)CH(CH₂)₂,—C(O)C₆H₅, —C(O)C₆H₄CH₃, —C(O)CH₂C₆H₅, —C(O)(imidazolyl) arenon-limiting examples of acyl groups. A “thioacyl” is defined in ananalogous manner, except that the oxygen atom of the group —C(O)R hasbeen replaced with a sulfur atom, —C(S)R. The term “aldehyde”corresponds to an alkane, as defined above, wherein at least one of thehydrogen atoms has been replaced with a —CHO group. When any of theseterms are used with the “substituted” modifier one or more hydrogen atom(including a hydrogen atom directly attached the carbonyl orthiocarbonyl group, if any) has been independently replaced by —OH, —F,—Cl, —Br, —I, —NH₂, —NO₂, —CO₂H, —CO₂CH₃, —CN, —SH, —OCH₃, —OCH₂CH₃,—C(O)CH₃, —NHCH₃, —NHCH₂CH₃, —N(CH₃)₂, —C(O)NH₂, —OC(O)CH₃, or—S(O)₂NH₂. The groups, —C(O)CH₂CF₃, —CO₂H (carboxyl), —CO₂CH₃(methylcarboxyl), —CO₂CH₂CH₃, —C(O)NH₂ (carbamoyl), and —CON(CH₃)₂, arenon-limiting examples of substituted acyl groups.

The term “alkoxy” when used without the “substituted” modifier refers tothe group —OR, in which R is an alkyl, as that term is defined above.Non-limiting examples of alkoxy groups include: —OCH₃ (methoxy),—OCH₂CH₃ (ethoxy), —OCH₂CH₂CH₃, —OCH(CH₃)₂ (isopropoxy), —O(CH₃)₃(tert-butoxy), —OCH(CH₂)₂, —O-cyclopentyl, and —O-cyclohexyl. The terms“alkenyloxy”, “alkynyloxy”, “aryloxy”, “aralkoxy”, “heteroaryloxy”,“heterocycloalkoxy”, and “acyloxy”, when used without the “substituted”modifier, refers to groups, defined as —OR, in which R is alkenyl,alkynyl, aryl, aralkyl, heteroaryl, heterocycloalkyl, and acyl,respectively. The term “alkoxydiyl” refers to the divalent group—O-alkanediyl-, —O-alkanediyl-O—, or -alkanediyl-O-alkanediyl-. The term“alkylthio” and “acylthio” when used without the “substituted” modifierrefers to the group —SR, in which R is an alkyl and acyl, respectively.The term “alcohol” corresponds to an alkane, as defined above, whereinat least one of the hydrogen atoms has been replaced with a hydroxygroup. The term “ether” corresponds to an alkane, as defined above,wherein at least one of the hydrogen atoms has been replaced with analkoxy group. When any of these terms is used with the “substituted”modifier one or more hydrogen atom has been independently replaced by—OH, —F, —Cl, —Br, —I, —NH₂, —NO₂, —CO₂H, —CO₂CH₃, —CN, —SH, —OCH₃,—OCH₂CH₃, —C(O)CH₃, —NHCH₃, —NHCH₂CH₃, —N(CH₃)₂, —C(O)NH₂, —OC(O)CH₃, or—S(O)₂NH₂.

The term “alkylamino” when used without the “substituted” modifierrefers to the group —NHR, in which R is an alkyl, as that term isdefined above. Non-limiting examples of alkylamino groups include:—NHCH₃ and —NHCH₂CH₃. The term “dialkylamino” when used without the“substituted” modifier refers to the group —NRR′, in which R and R′ canbe the same or different alkyl groups, or R and R′ can be taken togetherto represent an alkanediyl. Non-limiting examples of dialkylamino groupsinclude: —N(CH₃)₂, —N(CH₃)(CH₂CH₃), and N-pyrrolidinyl. The terms“alkoxyamino”, “alkenylamino”, “alkynylamino”, “arylamino”,“aralkylamino”, “heteroarylamino”, “heterocycloalkylamino” and“alkylsulfonylamino” when used without the “substituted” modifier,refers to groups, defined as —NHR, in which R is alkoxy, alkenyl,alkynyl, aryl, aralkyl, heteroaryl, heterocycloalkyl, and alkylsulfonyl,respectively. A non-limiting example of an arylamino group is —NHC₆H₅.The term “amido” (acylamino), when used without the “substituted”modifier, refers to the group —NHR, in which R is acyl, as that term isdefined above. A non-limiting example of an amido group is —NHC(O)CH₃.The term “alkylimino” when used without the “substituted” modifierrefers to the divalent group ═NR, in which R is an alkyl, as that termis defined above. The term “alkylaminodiyl” refers to the divalent group—NH-alkanediyl-, —NH-alkanediyl-NH—, or -alkanediyl-NH-alkanediyl-. Whenany of these terms is used with the “substituted” modifier one or morehydrogen atom has been independently replaced by —OH, —F, —Cl, —Br, —I,—NH₂, —NO₂, —CO₂H, —CO₂CH₃, —CN, —SH, —OCH₃, —OCH₂CH₃, —C(O)CH₃, —NHCH₃,—NHCH₂CH₃, —N(CH₃)₂, —C(O)NH₂, —OC(O)CH₃, or —S(O)₂NH₂. The groups—NHC(O)OCH₃ and —NHC(O)NHCH₃ are non-limiting examples of substitutedamido groups.

The terms “alkylsulfonyl” and “alkylsulfinyl” when used without the“substituted” modifier refers to the groups —S(O)₂R and —S(O)R,respectively, in which R is an alkyl, as that term is defined above. Theterms “alkenylsulfonyl”, “alkynylsulfonyl”, “arylsulfonyl”,“aralkylsulfonyl”, “heteroarylsulfonyl”, and “heterocycloalkylsulfonyl”are defined in an analogous manner. When any of these terms is used withthe “substituted” modifier one or more hydrogen atom has beenindependently replaced by —OH, —F, —Cl, —Br, —I, —NH₂, —NO₂, —CO₂H,—CO₂CH₃, —CN, —SH, —OCH₃, —OCH₂CH₃, —C(O)CH₃, —NHCH₃, —NHCH₂CH₃,—N(CH₃)₂, —C(O)NH₂, —OC(O)CH₃, or —S(O)₂NH₂.

The term “alkylphosphate” when used without the “substituted” modifierrefers to the group —OP(O)(OH)(OR), in which R is an alkyl, as that termis defined above. Non-limiting examples of alkylphosphate groupsinclude: —OP(O)(OH)(OMe) and —OP(O)(OH)(OEt). The term“dialkylphosphate” when used without the “substituted” modifier refersto the group —OP(O)(OR)(OR′), in which R and R′ can be the same ordifferent alkyl groups, or R and R′ can be taken together to representan alkanediyl. Non-limiting examples of dialkylphosphate groups include:—OP(O)(OMe)₂, —OP(O)(OEt)(OMe) and —OP(O)(OEt)₂. When any of these termsis used with the “substituted” modifier one or more hydrogen atom hasbeen independently replaced by —OH, —F, —Cl, —Br, —I, —NH₂, —NO₂, —CO₂H,—CO₂CH₃, —CN, —SH, —OCH₃, —OCH₂CH₃, —C(O)CH₃, —NHCH₃, —NHCH₂CH₃,—N(CH₃)₂, —C(O)NH₂, —OC(O)CH₃, or —S(O)₂NH₂.

The use of the word “a” or “an,” when used in conjunction with the term“comprising” in the claims and/or the specification may mean “one,” butit is also consistent with the meaning of “one or more,” “at least one,”and “one or more than one.”

Throughout this application, the term “about” is used to indicate that avalue includes the inherent variation of error for the device, themethod being employed to determine the value, or the variation thatexists among the study subjects.

As used herein, a “chiral auxiliary” refers to a removable chiral groupthat is capable of influencing the stereoselectivity of a reaction.Persons of skill in the art are familiar with such compounds, and manyare commercially available.

The terms “comprise,” “have” and “include” are open-ended linking verbs.Any forms or tenses of one or more of these verbs, such as “comprises,”“comprising,” “has,” “having,” “includes” and “including,” are alsoopen-ended. For example, any method that “comprises,” “has” or“includes” one or more steps is not limited to possessing only those oneor more steps and also covers other unlisted steps.

The term “effective,” as that term is used in the specification and/orclaims, means adequate to accomplish a desired, expected, or intendedresult. “Effective amount,” “Therapeutically effective amount” or“pharmaceutically effective amount” when used in the context of treatinga patient or subject with a compound means that amount of the compoundwhich, when administered to a subject or patient for treating a disease,is sufficient to effect such treatment for the disease.

As used herein, the term “IC₅₀” refers to an inhibitory dose which is50% of the maximum response obtained. This quantitative measureindicates how much of a particular drug or other substance (inhibitor)is needed to inhibit a given biological, biochemical or chemical process(or component of a process, i.e. an enzyme, cell, cell receptor ormicroorganism) by half.

An “isomer” of a first compound is a separate compound in which eachmolecule contains the same constituent atoms as the first compound, butwhere the configuration of those atoms in three dimensions differs.

As used herein, the term “patient” or “subject” refers to a livingmammalian organism, such as a human, monkey, cow, sheep, goat, dog, cat,mouse, rat, guinea pig, or transgenic species thereof. In certainembodiments, the patient or subject is a primate. Non-limiting examplesof human subjects are adults, juveniles, infants and fetuses.

As generally used herein “pharmaceutically acceptable” refers to thosecompounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues, organs, and/or bodily fluids of human beings andanimals without excessive toxicity, irritation, allergic response, orother problems or complications commensurate with a reasonablebenefit/risk ratio.

“Pharmaceutically acceptable salts” means salts of compounds of thepresent invention which are pharmaceutically acceptable, as definedabove, and which possess the desired pharmacological activity. Suchsalts include acid addition salts formed with inorganic acids such ashydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid, and the like; or with organic acids such as1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid,2-naphthalenesulfonic acid, 3-phenylpropionic acid,4,4′-methylenebis(3-hydroxy-2-ene-1-carboxylic acid),4-methylbicyclo[2.2.2]oct-2-ene-1-carboxylic acid, acetic acid,aliphatic mono- and dicarboxylic acids, aliphatic sulfuric acids,aromatic sulfuric acids, benzenesulfonic acid, benzoic acid,camphorsulfonic acid, carbonic acid, cinnamic acid, citric acid,cyclopentanepropionic acid, ethanesulfonic acid, fumaric acid,glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid,heptanoic acid, hexanoic acid, hydroxynaphthoic acid, lactic acid,laurylsulfuric acid, maleic acid, malic acid, malonic acid, mandelicacid, methanesulfonic acid, muconic acid, o-(4-hydroxybenzoyl)benzoicacid, oxalic acid, p-chlorobenzenesulfonic acid, phenyl-substitutedalkanoic acids, propionic acid, p-toluenesulfonic acid, pyruvic acid,salicylic acid, stearic acid, succinic acid, tartaric acid,tertiarybutylacetic acid, trimethylacetic acid, and the like.Pharmaceutically acceptable salts also include base addition salts whichmay be formed when acidic protons present are capable of reacting withinorganic or organic bases. Acceptable inorganic bases include sodiumhydroxide, sodium carbonate, potassium hydroxide, aluminum hydroxide andcalcium hydroxide. Acceptable organic bases include ethanolamine,diethanolamine, triethanolamine, tromethamine, N-methylglucamine and thelike. It should be recognized that the particular anion or cationforming a part of any salt of this invention is not critical, so long asthe salt, as a whole, is pharmacologically acceptable. Additionalexamples of pharmaceutically acceptable salts and their methods ofpreparation and use are presented in Handbook of Pharmaceutical Salts:Properties, and Use (P. H. Stahl & C. G. Wermuth eds., Verlag HelveticaChimica Acta, 2002).

The term “pharmaceutically acceptable carrier,” as used herein means apharmaceutically-acceptable material, composition or vehicle, such as aliquid or solid filler, diluent, excipient, solvent or encapsulatingmaterial, involved in carrying or transporting a chemical agent.

“Prevention” or “preventing” includes: (1) inhibiting the onset of adisease in a subject or patient which may be at risk and/or predisposedto the disease but does not yet experience or display any or all of thepathology or symptomatology of the disease, and/or (2) slowing the onsetof the pathology or symptomatology of a disease in a subject or patientwhich may be at risk and/or predisposed to the disease but does not yetexperience or display any or all of the pathology or symptomatology ofthe disease.

“Prodrug” means a compound that is convertible in vivo metabolicallyinto an inhibitor according to the present invention. The prodrug itselfmay or may not also have activity with respect to a given targetprotein. For example, a compound comprising a hydroxy group may beadministered as an ester that is converted by hydrolysis in vivo to thehydroxy compound. Suitable esters that may be converted in vivo intohydroxy compounds include acetates, citrates, lactates, phosphates,tartrates, malonates, oxalates, salicylates, propionates, succinates,fumarates, maleates, methylene-bis-β-hydroxynaphthoate, gentisates,isethionates, di-p-toluoyltartrates, methane-sulfonates,ethanesulfonates, benzenesulfonates, p-toluenesulfonates,cyclohexyl-sulfamates, quinates, esters of amino acids, and the like.Similarly, a compound comprising an amine group may be administered asan amide that is converted by hydrolysis in vivo to the amine compound.

A “stereoisomer” or “optical isomer” is an isomer of a given compound inwhich the same atoms are bonded to the same other atoms, but where theconfiguration of those atoms in three dimensions differs. “Enantiomers”are stereoisomers of a given compound that are mirror images of eachother, like left and right hands. “Diastereomers” are stereoisomers of agiven compound that are not enantiomers. Chiral molecules contain achiral center, also referred to as a stereocenter or stereogenic center,which is any point, though not necessarily an atom, in a moleculebearing groups such that an interchanging of any two groups leads to astereoisomer. In organic compounds, the chiral center is typically acarbon, phosphorus or sulfur atom, though it is also possible for otheratoms to be stereocenters in organic and inorganic compounds. A moleculecan have multiple stereocenters, giving it many stereoisomers. Incompounds whose stereoisomerism is due to tetrahedral stereogeniccenters (e.g., tetrahedral carbon), the total number of hypotheticallypossible stereoisomers will not exceed 2n, where n is the number oftetrahedral stereocenters. Molecules with symmetry frequently have fewerthan the maximum possible number of stereoisomers. A 50:50 mixture ofenantiomers is referred to as a racemic mixture. Alternatively, amixture of enantiomers can be enantiomerically enriched so that oneenantiomer is present in an amount greater than 50%. Typically,enantiomers and/or diastereomers can be resolved or separated usingtechniques known in the art. It is contemplated that that for anystereocenter or axis of chirality for which stereochemistry has not beendefined, that stereocenter or axis of chirality can be present in its Rform, S form, or as a mixture of the R and S forms, including racemicand non-racemic mixtures. As used herein, the phrase “substantially freefrom other stereoisomers” means that the composition contains ≤15%, morepreferably ≤10%, even more preferably ≤5%, or most preferably ≤1% ofanother stereoisomer(s).

“Treatment” or “treating” includes (1) inhibiting a disease in a subjector patient experiencing or displaying the pathology or symptomatology ofthe disease (e.g., arresting further development of the pathology and/orsymptomatology), (2) ameliorating a disease in a subject or patient thatis experiencing or displaying the pathology or symptomatology of thedisease (e.g., reversing the pathology and/or symptomatology), and/or(3) effecting any measurable decrease in a disease in a subject orpatient that is experiencing or displaying the pathology orsymptomatology of the disease.

Other abbreviations used herein are as follows: DMSO, dimethylsulfoxide; (COCl)₂, oxalyl chloride; EtN₃ or TEA, triethylamine; DMAP,dimethylaminopyridine; Et₂O, diethyl ether; n-PrCONHNH₂, butyric acidhydrazine; i-PrCONHNH₂, isobutyric acid hydrazine; c-PrCONHNH₂,cyclopropane carboxylic acid hydrazine; p-TsOH, p-toluenesulfonic acid;DMF, dimethylformamide; EDCl,1-ethyl-3-(3-dimethylaminopropyl)carbodiimide; NO, nitric oxide; iNOS,inducible nitric oxide synthase; COX-2, cyclooxygenase-2; FBS, fetalbovine serum; IFNγ or IFN-γ, interferon-γ; TNFα or TNF-α, tumor necrosisfactor-α; IL-1β, interleukin-1β; HO-1, inducible heme oxygenase.

The above definitions supersede any conflicting definition in any of thereference that is incorporated by reference herein. The fact thatcertain terms are defined, however, should not be considered asindicative that any term that is undefined is indefinite. Rather, allterms used are believed to describe the invention in terms such that oneof ordinary skill can appreciate the scope and practice the presentinvention.

II. Compounds and Synthetic Methods

The compounds provided by the present disclosure are shown above in thesummary of the invention, in the claims, and in the sections below. Theymay be made using the methods outlined in the Examples section. Thesemethods can be further modified and optimized using the principles andtechniques of organic chemistry as applied by a person skilled in theart. Such principles and techniques are taught, for example, in March'sAdvanced Organic Chemistry: Reactions, Mechanisms, and Structure (2007),which is incorporated by reference herein.

Compounds of the invention may contain one or moreasymmetrically-substituted carbon or nitrogen atoms, and may be isolatedin optically active or racemic form. Thus, all chiral, diastereomeric,racemic form, epimeric form, and all geometric isomeric forms of achemical formula are intended, unless the specific stereochemistry orisomeric form is specifically indicated. Compounds may occur asracemates and racemic mixtures, single enantiomers, diastereomericmixtures and individual diastereomers. In some embodiments, a singlediastereomer is obtained. The chiral centers of the compounds of thepresent invention can have the S or the R configuration.

Chemical formulas used to represent compounds of the invention willtypically only show one of possibly several different tautomers. Forexample, many types of ketone groups are known to exist in equilibriumwith corresponding enol groups. Similarly, many types of imine groupsexist in equilibrium with enamine groups. Regardless of which tautomeris depicted for a given compound, and regardless of which one is mostprevalent, all tautomers of a given chemical formula are intended.

Atoms making up the compounds of the present invention are intended toinclude all isotopic forms of such atoms. Compounds of the presentinvention include those with one or more atoms that have beenisotopically modified or enriched, in particular those withpharmaceutically acceptable isotopes or those useful forpharmaceutically research. Isotopes, as used herein, include those atomshaving the same atomic number but different mass numbers. By way ofgeneral example and without limitation, isotopes of hydrogen includedeuterium and tritium, and isotopes of carbon include ¹³C and ¹⁴C.Similarly, it is contemplated that one or more carbon atom(s) of acompound of the present invention may be replaced by a silicon atom(s).Furthermore, it is contemplated that one or more oxygen atom(s) of acompound of the present invention may be replaced by a sulfur orselenium atom(s).

Compounds of the present invention may also exist in prodrug form. Sinceprodrugs are known to enhance numerous desirable qualities ofpharmaceuticals (e.g., solubility, bioavailability, manufacturing,etc.), the compounds employed in some methods of the invention may, ifdesired, be delivered in prodrug form. Thus, the invention contemplatesprodrugs of compounds of the present invention as well as methods ofdelivering prodrugs. Prodrugs of the compounds employed in the inventionmay be prepared by modifying functional groups present in the compoundin such a way that the modifications are cleaved, either in routinemanipulation or in vivo, to the parent compound. Accordingly, prodrugsinclude, for example, compounds described herein in which a hydroxy,amino, or carboxy group is bonded to any group that, when the prodrug isadministered to a subject, cleaves to form a hydroxy, amino, orcarboxylic acid, respectively.

It should be recognized that the particular anion or cation forming apart of any salt of this invention is not critical, so long as the salt,as a whole, is pharmacologically acceptable. Additional examples ofpharmaceutically acceptable salts and their methods of preparation anduse are presented in Handbook of Pharmaceutical Salts: Properties, andUse (2002), which is incorporated herein by reference.

It should be further recognized that the compounds of the presentinvention include those that have been further modified to comprisesubstituents that are convertible to hydrogen in vivo. This includesthose groups that may be convertible to a hydrogen atom by enzymologicalor chemical means including, but not limited to, hydrolysis andhydrogenolysis. Examples include hydrolyzable groups, such as acylgroups, groups having an oxycarbonyl group, amino acid residues, peptideresidues, o-nitrophenylsulfenyl, trimethylsilyl, tetrahydropyranyl,diphenylphosphinyl, and the like. Examples of acyl groups includeformyl, acetyl, trifluoroacetyl, and the like. Examples of groups havingan oxycarbonyl group include ethoxycarbonyl, tert-butoxycarbonyl(—C(O)OC(CH₃)₃, Boc), benzyloxycarbonyl, p-methoxy-benzyloxycarbonyl,vinyloxycarbonyl, β-(p-toluenesulfonyl)ethoxycarbonyl, and the like.Suitable amino acid residues include, but are not limited to, residuesof Gly (glycine), Ala (alanine), Arg (arginine), Asn (asparagine), Asp(aspartic acid), Cys (cysteine), Glu (glutamic acid), His (histidine),Ile (isoleucine), Leu (leucine), Lys (lysine), Met (methionine), Phe(phenylalanine), Pro (proline), Ser (serine), Thr (threonine), Trp(tryptophan), Tyr (tyrosine), Val (valine), Nva (norvaline), Hse(homoserine), 4-Hyp (4-hydroxyproline), 5-Hyl (5-hydroxylysine), Orn(ornithine) and β-Ala. Examples of suitable amino acid residues alsoinclude amino acid residues that are protected with a protecting group.Examples of suitable protecting groups include those typically employedin peptide synthesis, including acyl groups (such as formyl and acetyl),arylmethoxycarbonyl groups (such as benzyloxycarbonyl andp-nitrobenzyloxycarbonyl), tert-butoxycarbonyl groups (—C(O)OC(CH₃)₃,Boc), and the like. Suitable peptide residues include peptide residuescomprising two to five amino acid residues. The residues of these aminoacids or peptides can be present in stereochemical configurations of theD-form, the L-form or mixtures thereof. In addition, the amino acid orpeptide residue may have an asymmetric carbon atom. Examples of suitableamino acid residues having an asymmetric carbon atom include residues ofAla, Leu, Phe, Trp, Nva, Val, Met, Ser, Lys, Thr and Tyr. Peptideresidues having an asymmetric carbon atom include peptide residueshaving one or more constituent amino acid residues having an asymmetriccarbon atom. Examples of suitable amino acid protecting groups includethose typically employed in peptide synthesis, including acyl groups(such as formyl and acetyl), arylmethoxycarbonyl groups (such asbenzyloxycarbonyl and p-nitrobenzyloxycarbonyl), tert-butoxycarbonylgroups (—C(O)OC(CH₃)₃), and the like. Other examples of substituents“convertible to hydrogen in vivo” include reductively eliminablehydrogenolyzable groups. Examples of suitable reductively eliminablehydrogenolyzable groups include, but are not limited to, arylsulfonylgroups (such as o-toluenesulfonyl); methyl groups substituted withphenyl or benzyloxy (such as benzyl, trityl and benzyloxymethyl);arylmethoxycarbonyl groups (such as benzyloxycarbonyl ando-methoxy-benzyloxycarbonyl); and haloethoxycarbonyl groups (such asβ,β,β-trichloroethoxycarbonyl and β-iodoethoxycarbonyl).

Compounds of the invention may also have the advantage that they may bemore efficacious than, be less toxic than, be longer acting than, bemore potent than, produce fewer side effects than, be more easilyabsorbed than, and/or have a better pharmacokinetic profile (e.g.,higher oral bioavailability and/or lower clearance) than, and/or haveother useful pharmacological, physical, or chemical properties over,compounds known in the prior art, whether for use in the indicationsstated herein or otherwise.

III. Biological Activity

Assay results for the suppression of IFNγ-induced NO production areshown for several of the compounds of the present invention in Table 1below. In the right-hand column of this table under the RAW264.7heading, the results are compared to those of bardoxolone methyl (RTA402, CDDO-Me). Details regarding this assay are provided in the Examplessection below.

TABLE 1 Suppression of IFNγ-Induced NO Production. RAW264.7 Relative NOCompound No. Molecular Structure MW NO IC₅₀ (nM) IC₅₀ TX63384

529.72 2.0 0.6 TX63475

557.78 5.7 4.1 TX63476

557.78 5.4 3.9 TX63477

555.76 3.3 2.4 TX63478

559.75 1.8 1.3 TX63479

515.69 1.1 0.8 TX63501

529.71 1.0 0.6 TX63593

543.74 1.7 0.7IV. Diseases Associated with Inflammation and/or Oxidative Stress

Inflammation is a biological process that provides resistance toinfectious or parasitic organisms and the repair of damaged tissue.Inflammation is commonly characterized by localized vasodilation,redness, swelling, and pain, the recruitment of leukocytes to the siteof infection or injury, production of inflammatory cytokines such asTNF-α and IL-1, and production of reactive oxygen or nitrogen speciessuch as hydrogen peroxide, superoxide and peroxynitrite. In later stagesof inflammation, tissue remodeling, angiogenesis, and scar formation(fibrosis) may occur as part of the wound healing process. Under normalcircumstances, the inflammatory response is regulated and temporary andis resolved in an orchestrated fashion once the infection or injury hasbeen dealt with adequately. However, acute inflammation can becomeexcessive and life-threatening if regulatory mechanisms fail.Alternatively, inflammation can become chronic and cause cumulativetissue damage or systemic complications. Based at least on the evidencepresented above, the compounds of this invention may be used in thetreatment or prevention of inflammation or diseases associated withinflammation.

Many serious and intractable human diseases involve dysregulation ofinflammatory processes, including diseases such as cancer,atherosclerosis, and diabetes, which were not traditionally viewed asinflammatory conditions. In the case of cancer, the inflammatoryprocesses are associated with tumor formation, progression, metastasis,and resistance to therapy. Atherosclerosis, long viewed as a disorder oflipid metabolism, is now understood to be primarily an inflammatorycondition, with activated macrophages playing an important role in theformation and eventual rupture of atherosclerotic plaques. Activation ofinflammatory signaling pathways has also been shown to play a role inthe development of insulin resistance, as well as in the peripheraltissue damage associated with diabetic hyperglycemia. Excessiveproduction of reactive oxygen species and reactive nitrogen species suchas superoxide, hydrogen peroxide, nitric oxide, and peroxynitrite is ahallmark of inflammatory conditions. Evidence of dysregulatedperoxynitrite production has been reported in a wide variety of diseases(Szabo et al., 2007; Schulz et al., 2008; Forstermann, 2006; Pall,2007).

Autoimmune diseases such as rheumatoid arthritis, lupus, psoriasis, andmultiple sclerosis involve inappropriate and chronic activation ofinflammatory processes in affected tissues, arising from dysfunction ofself vs. non-self recognition and response mechanisms in the immunesystem. In neurodegenerative diseases such as Alzheimer's andParkinson's diseases, neural damage is correlated with activation ofmicroglia and elevated levels of pro-inflammatory proteins such asinducible nitric oxide synthase (iNOS). Chronic organ failure such asrenal failure, heart failure, liver failure, and chronic obstructivepulmonary disease is closely associated with the presence of chronicoxidative stress and inflammation, leading to the development offibrosis and eventual loss of organ function. Oxidative stress invascular endothelial cells, which line major and minor blood vessels,can lead to endothelial dysfunction and is believed to be an importantcontributing factor in the development of systemic cardiovasculardisease, complications of diabetes, chronic kidney disease and otherforms of organ failure, and a number of other aging-related diseasesincluding degenerative diseases of the central nervous system and theretina.

Many other disorders involve oxidative stress and inflammation inaffected tissues, including inflammatory bowel disease; inflammatoryskin diseases; mucositis related to radiation therapy and chemotherapy;eye diseases such as uveitis, glaucoma, macular degeneration, andvarious forms of retinopathy; transplant failure and rejection;ischemia-reperfusion injury; chronic pain; degenerative conditions ofthe bones and joints including osteoarthritis and osteoporosis; asthmaand cystic fibrosis; seizure disorders; and neuropsychiatric conditionsincluding schizophrenia, depression, bipolar disorder, post-traumaticstress disorder, attention deficit disorders, autism-spectrum disorders,and eating disorders such as anorexia nervosa. Dysregulation ofinflammatory signaling pathways is believed to be a major factor in thepathology of muscle wasting diseases including muscular dystrophy andvarious forms of cachexia.

A variety of life-threatening acute disorders also involve dysregulatedinflammatory signaling, including acute organ failure involving thepancreas, kidneys, liver, or lungs, myocardial infarction or acutecoronary syndrome, stroke, septic shock, trauma, severe burns, andanaphylaxis.

Many complications of infectious diseases also involve dysregulation ofinflammatory responses. Although an inflammatory response can killinvading pathogens, an excessive inflammatory response can also be quitedestructive and in some cases can be a primary source of damage ininfected tissues. Furthermore, an excessive inflammatory response canalso lead to systemic complications due to overproduction ofinflammatory cytokines such as TNF-α and IL-1. This is believed to be afactor in mortality arising from severe influenza, severe acuterespiratory syndrome, and sepsis.

The aberrant or excessive expression of either iNOS or cyclooxygenase-2(COX-2) has been implicated in the pathogenesis of many diseaseprocesses. For example, it is clear that NO is a potent mutagen (Tamirand Tannebaum, 1996), and that nitric oxide can also activate COX-2(Salvemini et al., 1994). Furthermore, there is a marked increase iniNOS in rat colon tumors induced by the carcinogen, azoxymethane(Takahashi et al., 1997). A series of synthetic triterpenoid analogs ofoleanolic acid have been shown to be powerful inhibitors of cellularinflammatory processes, such as the induction by IFN-γ of induciblenitric oxide synthase (iNOS) and of COX-2 in mouse macrophages. SeeHonda et al. (2000a); Honda et al. (2000b), and Honda et al. (2002),which are all incorporated herein by reference.

In one aspect, compounds disclosed herein are characterized by theirability to inhibit the production of nitric oxide in macrophage-derivedRAW 264.7 cells induced by exposure to γ-interferon. They are furthercharacterized by their ability to induce the expression of antioxidantproteins such as NQO1 and reduce the expression of pro-inflammatoryproteins such as COX-2 and inducible nitric oxide synthase (iNOS). Theseproperties are relevant to the treatment of a wide array of diseases anddisorders involving oxidative stress and dysregulation of inflammatoryprocesses including cancer, complications from localized or total-bodyexposure to ionizing radiation, mucositis resulting from radiationtherapy or chemotherapy, autoimmune diseases, cardiovascular diseasesincluding atherosclerosis, ischemia-reperfusion injury, acute andchronic organ failure including renal failure and heart failure,respiratory diseases, diabetes and complications of diabetes, severeallergies, transplant rejection, graft-versus-host disease,neurodegenerative diseases, diseases of the eye and retina, acute andchronic pain, degenerative bone diseases including osteoarthritis andosteoporosis, inflammatory bowel diseases, dermatitis and other skindiseases, sepsis, burns, seizure disorders, and neuropsychiatricdisorders.

Without being bound by theory, the activation of theantioxidant/anti-inflammatory Keap1/Nrf2/ARE pathway is believed to beimplicated in both the anti-inflammatory and anti-carcinogenicproperties of the compounds disclosed herein.

In another aspect, compounds disclosed herein may be used for treating asubject having a condition caused by elevated levels of oxidative stressin one or more tissues. Oxidative stress results from abnormally high orprolonged levels of reactive oxygen species such as superoxide, hydrogenperoxide, nitric oxide, and peroxynitrite (formed by the reaction ofnitric oxide and superoxide). The oxidative stress may be accompanied byeither acute or chronic inflammation. The oxidative stress may be causedby mitochondrial dysfunction, by activation of immune cells such asmacrophages and neutrophils, by acute exposure to an external agent suchas ionizing radiation or a cytotoxic chemotherapy agent (e.g.,doxorubicin), by trauma or other acute tissue injury, byischemia/reperfusion, by poor circulation or anemia, by localized orsystemic hypoxia or hyperoxia, by elevated levels of inflammatorycytokines and other inflammation-related proteins, and/or by otherabnormal physiological states such as hyperglycemia or hypoglycemia.

In animal models of many such conditions, stimulating expression ofinducible heme oxygenase (HO-1), a target gene of the Nrf2 pathway, hasbeen shown to have a significant therapeutic effect including models ofmyocardial infarction, renal failure, transplant failure and rejection,stroke, cardiovascular disease, and autoimmune disease (e.g., Sacerdotiet al., 2005; Abraham & Kappas, 2005; Bach, 2006; Araujo et al., 2003;Liu et al., 2006; Ishikawa et al., 2001; Kruger et al., 2006; Satoh etal., 2006; Zhou et al., 2005; Morse and Choi, 2005; Morse and Choi,2002). This enzyme breaks free heme down into iron, carbon monoxide(CO), and biliverdin (which is subsequently converted to the potentantioxidant molecule, bilirubin).

In another aspect, compounds of this invention may be used in preventingor treating tissue damage or organ failure, acute and chronic, resultingfrom oxidative stress exacerbated by inflammation. Examples of diseasesthat fall in this category include: heart failure, liver failure,transplant failure and rejection, renal failure, pancreatitis, fibroticlung diseases (cystic fibrosis, COPD, and idiopathic pulmonary fibrosis,among others), diabetes (including complications), atherosclerosis,ischemia-reperfusion injury, glaucoma, stroke, autoimmune disease,autism, macular degeneration, and muscular dystrophy. For example, inthe case of autism, studies suggest that increased oxidative stress inthe central nervous system may contribute to the development of thedisease (Chauhan and Chauhan, 2006).

Evidence also links oxidative stress and inflammation to the developmentand pathology of many other disorders of the central nervous system,including psychiatric disorders such as psychosis, major depression, andbipolar disorder; seizure disorders such as epilepsy; pain and sensorysyndromes such as migraine, neuropathic pain or tinnitus; and behavioralsyndromes such as the attention deficit disorders. See, e.g., Dickersonet al., 2007; Hanson et al., 2005; Kendall-Tackett, 2007; Lencz et al.,2007; Dudhgaonkar et al., 2006; Lee et al., 2007; Morris et al., 2002;Ruster et al., 2005; McIver et al., 2005; Sarchielli et al., 2006;Kawakami et al., 2006; Ross et al., 2003, which are all incorporated byreference herein. For example, elevated levels of inflammatorycytokines, including TNF, interferon-γ, and IL-6, are associated withmajor mental illness (Dickerson et al., 2007). Microglial activation hasalso been linked to major mental illness. Therefore, downregulatinginflammatory cytokines and inhibiting excessive activation of microgliacould be beneficial in patients with schizophrenia, major depression,bipolar disorder, autism-spectrum disorders, and other neuropsychiatricdisorders.

Accordingly, in pathologies involving oxidative stress alone oroxidative stress exacerbated by inflammation, treatment may compriseadministering to a subject a therapeutically effective amount of acompound of this invention, such as those described above or throughoutthis specification. Treatment may be administered preventively, inadvance of a predictable state of oxidative stress (e.g., organtransplantation or the administration of radiation therapy to a cancerpatient), or it may be administered therapeutically in settingsinvolving established oxidative stress and inflammation.

The compounds disclosed herein may be generally applied to the treatmentof inflammatory conditions, such as sepsis, dermatitis, autoimmunedisease and osteoarthritis. In one aspect, the compounds of thisinvention may be used to treat inflammatory pain and/or neuropathicpain, for example, by inducing Nrf2 and/or inhibiting NF-κB.

In some embodiments, the compounds disclosed herein may be used in thetreatment and prevention of diseases such as cancer, inflammation,Alzheimer's disease, Parkinson's disease, multiple sclerosis, autism,amyotrophic lateral sclerosis, Huntington's disease, autoimmune diseasessuch as rheumatoid arthritis, lupus, Crohn's disease and psoriasis,inflammatory bowel disease, all other diseases whose pathogenesis isbelieved to involve excessive production of either nitric oxide orprostaglandins, and pathologies involving oxidative stress alone oroxidative stress exacerbated by inflammation.

Another aspect of inflammation is the production of inflammatoryprostaglandins such as prostaglandin E. These molecules promotevasodilation, plasma extravasation, localized pain, elevatedtemperature, and other symptoms of inflammation. The inducible form ofthe enzyme COX-2 is associated with their production, and high levels ofCOX-2 are found in inflamed tissues. Consequently, inhibition of COX-2may relieve many symptoms of inflammation and a number of importantanti-inflammatory drugs (e.g., ibuprofen and celecoxib) act byinhibiting COX-2 activity. Recent research, however, has demonstratedthat a class of cyclopentenone prostaglandins (cyPGs) (e.g., 15-deoxyprostaglandin J2, a.k.a. PGJ2) plays a role in stimulating theorchestrated resolution of inflammation (e.g., Rajakariar et al., 2007).COX-2 is also associated with the production of cyclopentenoneprostaglandins. Consequently, inhibition of COX-2 may interfere with thefull resolution of inflammation, potentially promoting the persistenceof activated immune cells in tissues and leading to chronic,“smoldering” inflammation. This effect may be responsible for theincreased incidence of cardiovascular disease in patients usingselective COX-2 inhibitors for long periods of time.

In one aspect, the compounds disclosed herein may be used to control theproduction of pro-inflammatory cytokines within the cell by selectivelyactivating regulatory cysteine residues (RCRs) on proteins that regulatethe activity of redox-sensitive transcription factors. Activation ofRCRs by cyPGs has been shown to initiate a pro-resolution program inwhich the activity of the antioxidant and cytoprotective transcriptionfactor Nrf2 is potently induced and the activities of the pro-oxidantand pro-inflammatory transcription factors NF-κB and the STATs aresuppressed. In some embodiments, this increases the production ofantioxidant and reductive molecules (NQO1, HO-1, SOD1, γ-GCS) anddecreases oxidative stress and the production of pro-oxidant andpro-inflammatory molecules (iNOS, COX-2, TNF-α). In some embodiments,the compounds of this invention may cause the cells that host theinflammatory event to revert to a non-inflammatory state by promotingthe resolution of inflammation and limiting excessive tissue damage tothe host.

V. Pharmaceutical Formulations and Routes of Administration

The compounds of the present disclosure may be administered by a varietyof methods, e.g., orally or by injection (e.g. subcutaneous,intravenous, intraperitoneal, etc.). Depending on the route ofadministration, the active compounds may be coated in a material toprotect the compound from the action of acids and other naturalconditions which may inactivate the compound. They may also beadministered by continuous perfusion/infusion of a disease or woundsite.

To administer the therapeutic compound by other than parenteraladministration, it may be necessary to coat the compound with, orco-administer the compound with, a material to prevent its inactivation.For example, the therapeutic compound may be administered to a patientin an appropriate carrier, for example, liposomes, or a diluent.Pharmaceutically acceptable diluents include saline and aqueous buffersolutions. Liposomes include water-in-oil-in-water CGF emulsions as wellas conventional liposomes (Strejan et al., 1984).

The therapeutic compound may also be administered parenterally,intraperitoneally, intraspinally, or intracerebrally. Dispersions can beprepared in glycerol, liquid polyethylene glycols, and mixtures thereofand in oils. Under ordinary conditions of storage and use, thesepreparations may contain a preservative to prevent the growth ofmicroorganisms.

Pharmaceutical compositions suitable for injectable use include: sterileaqueous solutions (where water soluble), dispersions, and sterilepowders for the extemporaneous preparation of sterile injectablesolutions or dispersion. See for example U.S. patent application by J.Zhang, entitled “Amorphous Solid Dispersions of CDDO-Me for DelayedRelease Oral Dosage Compositions,” filed Feb. 13, 2009, which isincorporated herein by reference. In all cases, the composition must besterile and must be fluid to the extent that easy syringability exists.It must be stable under the conditions of manufacture and storage andmust be preserved against the contaminating action of microorganismssuch as bacteria and fungi. The carrier can be a solvent or dispersionmedium containing, for example, water, ethanol, polyol (such as,glycerol, propylene glycol, and liquid polyethylene glycol, and thelike), suitable mixtures thereof, and vegetable oils. The properfluidity can be maintained, for example, by the use of a coating such aslecithin, by the maintenance of the required particle size in the caseof dispersion and by the use of surfactants. Prevention of the action ofmicroorganisms can be achieved by various antibacterial and antifungalagents, for example, parabens, chlorobutanol, phenol, ascorbic acid,thimerosal, and the like. In many cases, it will be preferable toinclude isotonic agents, for example, sugars, sodium chloride, orpolyalcohols such as mannitol and sorbitol, in the composition.Prolonged absorption of the injectable compositions can be brought aboutby including in the composition an agent which delays absorption, forexample, aluminum monostearate or gelatin.

Sterile injectable solutions can be prepared by incorporating thetherapeutic compound in the required amount in an appropriate solventwith one or a combination of ingredients enumerated above, as required,followed by filtered sterilization. Generally, dispersions are preparedby incorporating the therapeutic compound into a sterile carrier whichcontains a basic dispersion medium and the required other ingredientsfrom those enumerated above. In the case of sterile powders for thepreparation of sterile injectable solutions, the preferred methods ofpreparation are vacuum drying and freeze-drying which yields a powder ofthe active ingredient (i.e., the therapeutic compound) plus anyadditional desired ingredient from a previously sterile-filteredsolution thereof.

The therapeutic compound can be orally administered, for example, withan inert diluent or an assimilable edible carrier. The therapeuticcompound and other ingredients may also be enclosed in a hard or softshell gelatin capsule, compressed into tablets, or incorporated directlyinto the subject's diet. For oral therapeutic administration, thetherapeutic compound may be incorporated with excipients and used in theform of ingestible tablets, buccal tablets, troches, capsules, elixirs,suspensions, syrups, wafers, and the like. The percentage of thetherapeutic compound in the compositions and preparations may, ofcourse, be varied. The amount of the therapeutic compound in suchtherapeutically useful compositions is such that a suitable dosage willbe obtained.

It is especially advantageous to formulate parenteral compositions indosage unit form for ease of administration and uniformity of dosage.Dosage unit form as used herein refers to physically discrete unitssuited as unitary dosages for the subjects to be treated; each unitcontaining a predetermined quantity of therapeutic compound calculatedto produce the desired therapeutic effect in association with therequired pharmaceutical carrier. The specification for the dosage unitforms of the invention are dictated by and directly dependent on (a) theunique characteristics of the therapeutic compound and the particulartherapeutic effect to be achieved, and (b) the limitations inherent inthe art of compounding such a therapeutic compound for the treatment ofa selected condition in a patient.

The therapeutic compound may also be administered topically to the skin,eye, or mucosa. Alternatively, if local delivery to the lungs is desiredthe therapeutic compound may be administered by inhalation in adry-powder or aerosol formulation.

Active compounds are administered at a therapeutically effective dosagesufficient to treat a condition associated with a condition in apatient. For example, the efficacy of a compound can be evaluated in ananimal model system that may be predictive of efficacy in treating thedisease in humans, such as the model systems shown in the examples anddrawings.

The actual dosage amount of a compound of the present disclosure orcomposition comprising a compound of the present disclosure administeredto a subject may be determined by physical and physiological factorssuch as age, sex, body weight, severity of condition, the type ofdisease being treated, previous or concurrent therapeutic interventions,idiopathy of the subject and on the route of administration. Thesefactors may be determined by a skilled artisan. The practitionerresponsible for administration will typically determine theconcentration of active ingredient(s) in a composition and appropriatedose(s) for the individual subject. The dosage may be adjusted by theindividual physician in the event of any complication.

An effective amount typically will vary from about 0.001 mg/kg to about1000 mg/kg, from about 0.01 mg/kg to about 750 mg/kg, from about 100mg/kg to about 500 mg/kg, from about 1.0 mg/kg to about 250 mg/kg, fromabout 10.0 mg/kg to about 150 mg/kg in one or more dose administrationsdaily, for one or several days (depending of course of the mode ofadministration and the factors discussed above). Other suitable doseranges include 1 mg to 10000 mg per day, 100 mg to 10000 mg per day, 500mg to 10000 mg per day, and 500 mg to 1000 mg per day. In someparticular embodiments, the amount is less than 10,000 mg per day with arange of 750 mg to 9000 mg per day.

The effective amount may be less than 1 mg/kg/day, less than 500mg/kg/day, less than 250 mg/kg/day, less than 100 mg/kg/day, less than50 mg/kg/day, less than 25 mg/kg/day or less than 10 mg/kg/day. It mayalternatively be in the range of 1 mg/kg/day to 200 mg/kg/day. Forexample, regarding treatment of diabetic patients, the unit dosage maybe an amount that reduces blood glucose by at least 40% as compared toan untreated subject. In another embodiment, the unit dosage is anamount that reduces blood glucose to a level that is ±10% of the bloodglucose level of a non-diabetic subject.

In other non-limiting examples, a dose may also comprise from about 1micro-gram/kg/body weight, about 5 microgram/kg/body weight, about 10microgram/kg/body weight, about 50 microgram/kg/body weight, about 100microgram/kg/body weight, about 200 microgram/kg/body weight, about 350microgram/kg/body weight, about 500 microgram/kg/body weight, about 1milligram/kg/body weight, about 5 milli-gram/kg/body weight, about 10milligram/kg/body weight, about 50 milligram/kg/body weight, about 100milligram/kg/body weight, about 200 milligram/kg/body weight, about 350milligram/kg/body weight, about 500 milligram/kg/body weight, to about1000 mg/kg/body weight or more per administration, and any rangederivable therein. In non-limiting examples of a derivable range fromthe numbers listed herein, a range of about 5 mg/kg/body weight to about100 mg/kg/body weight, about 5 microgram/kg/body weight to about 500milligram/kg/body weight, etc., can be administered, based on thenumbers described above.

In certain embodiments, a pharmaceutical composition of the presentdisclosure may comprise, for example, at least about 0.1% of a compoundof the present disclosure. In other embodiments, the compound of thepresent disclosure may comprise between about 2% to about 75% of theweight of the unit, or between about 25% to about 60%, for example, andany range derivable therein.

Single or multiple doses of the agents are contemplated. Desired timeintervals for delivery of multiple doses can be determined by one ofordinary skill in the art employing no more than routineexperimentation. As an example, subjects may be administered two dosesdaily at approximately 12 hour intervals. In some embodiments, the agentis administered once a day.

The agent(s) may be administered on a routine schedule. As used herein aroutine schedule refers to a predetermined designated period of time.The routine schedule may encompass periods of time which are identicalor which differ in length, as long as the schedule is predetermined. Forinstance, the routine schedule may involve administration twice a day,every day, every two days, every three days, every four days, every fivedays, every six days, a weekly basis, a monthly basis or any set numberof days or weeks there-between. Alternatively, the predetermined routineschedule may involve administration on a twice daily basis for the firstweek, followed by a daily basis for several months, etc. In otherembodiments, the invention provides that the agent(s) may be takenorally and that the timing of which is or is not dependent upon foodintake. Thus, for example, the agent can be taken every morning and/orevery evening, regardless of when the subject has eaten or will eat.

VI. Combination Therapy

In addition to being used as a monotherapy, the compounds of the presentinvention may also find use in combination therapies. Effectivecombination therapy may be achieved with a single composition orpharmacological formulation that includes both agents, or with twodistinct compositions or formulations, administered at the same time,wherein one composition includes a compound of this invention, and theother includes the second agent(s). Alternatively, the therapy mayprecede or follow the other agent treatment by intervals ranging fromminutes to months.

Non-limiting examples of such combination therapy include combination ofone or more compounds of the invention with another anti-inflammatoryagent, a chemotherapeutic agent, radiation therapy, an antidepressant,an antipsychotic agent, an anticonvulsant, a mood stabilizer, ananti-infective agent, an antihypertensive agent, a cholesterol-loweringagent or other modulator of blood lipids, an agent for promoting weightloss, an antithrombotic agent, an agent for treating or preventingcardiovascular events such as myocardial infarction or stroke, anantidiabetic agent, an agent for reducing transplant rejection orgraft-versus-host disease, an anti-arthritic agent, an analgesic agent,an anti-asthmatic agent or other treatment for respiratory diseases, oran agent for treatment or prevention of skin disorders. Compounds of theinvention may be combined with agents designed to improve a patient'simmune response to cancer, including (but not limited to) cancervaccines. See Lu et al. (2011), which is incorporated herein byreference.

VII. Examples

The following examples are included to demonstrate preferred embodimentsof the invention. It should be appreciated by those of skill in the artthat the techniques disclosed in the examples which follow representtechniques discovered by the inventor to function well in the practiceof the invention, and thus can be considered to constitute preferredmodes for its practice. However, those of skill in the art should, inlight of the present disclosure, appreciate that many changes can bemade in the specific embodiments which are disclosed and still obtain alike or similar result without departing from the spirit and scope ofthe invention.

Methods and Materials

Nitric Oxide Production and Cell Viability Assay. RAW264.7 mousemacrophages were plated in 96-well plates at 30,000 cells/well intriplicate in RPMI1640+0.5% FBS and incubated at 37° C. with 5% CO₂. Onthe next day, cells were pre-treated with DMSO or drug (0-200 nM doserange) for 2 hours, and then treated with recombinant mouse IFNγ (R&DSystems) for 24 hours. Nitric Oxide concentration in media wasdetermined using the Griess reagent system (Promega). Cell viability wasdetermined using WST-1 reagent (Roche). IC₅₀ values were determinedbased on the suppression of IFNγ induced Nitric Oxide productionnormalized to cell viability.

NQO1-ARE Luciferase Reporter Assay. This assay allows for quantitativeassessment of the endogenous activity of the Nrf2 transcription factorin cultured mammalian cells. Expression of Firefly luciferase fromNQO1-ARE luciferase reporter plasmid is controlled by binding of Nrf2 toa specific enhancer sequence corresponding to the antioxidant responseelement (ARE) that was identified in the promoter region of the humanNADPH:quinone oxidoreductase 1 (NQO1) gene (Xie et al., 1995). Theplasmid was constructed by inserting a sequence:

(SEQ ID NO: 1) 5′-CAGTCACAGTGACTCAGCAGAATCTG-3′encompassing the human NQO1-ARE into the pLuc-MCS vector usingHindIII/XhoI cloning sites (GenScript Corp., Piscataway, N.J.). Theassay is performed in HuH7 cells maintained in DMEM (Invitrogen)supplemented with 10% FBS and 100 U/ml (each) of penicillin andstreptomycin. For the assay, cells are plated in 96-well plates at17,000 cells per well. Twenty four hours later, the cells areco-transfected with 50 ng each of NQO1-ARE reporter plasmid and pRL-TKplasmid using Lipofectamine 2000 transfection reagent (Invitrogen).pRL-TK plasmid constitutively expresses Renilla luciferase and is usedas an internal control for normalization of transfection levels. Thirtyhours after transfection, the cells are treated with compounds (atconcentrations ranging from 0 to 1 μM) for eighteen hours. Firefly andRenilla luciferase activity is assayed by Dual-Glo Luciferase Assay(Promega Corp., Madison, Wis.), the luminescence signal is measured onan L-Max II luminometer (Molecular Devices). Firefly luciferase activityis normalized to the Renilla activity, and fold induction over a vehiclecontrol (DMSO) of normalized Firefly activity is calculated. The foldinduction at 62.5 nM concentration is used for comparing relativepotencies of compounds to induce Nrf2 transcriptional activity. See Xieet al., 1995, which is incorporated herein by reference.

Synthetic Schemes, Reagents and Yields

Synthesis and Characterization of Compounds and Intermediates

Compound 1: Compound RTA 401 (1.00 g, 2.03 mmol) was dissolved in CH₂Cl₂(20 mL), and the solution was cooled to 0° C. Oxalyl chloride (0.55 mL,6.50 mmol) was added, followed by DMF (2 drops). The reaction mixturewas stirred at room temperature for 2 h, then the reaction mixture wasconcentrated. The residue was azeotroped 2× with CH₂Cl₂ to give compound1 as a yellow foam, which was used directly in the next step.

Compound 2: Compound 1 (2.03 mmol) was dissolved in Et₂O (20 mL), andthe solution was cooled to 0° C. To the reaction mixture were added Et₃N(0.565 mL, 4.05 mmoL) and a solution of acethydrazide (226 mg, 3.05mmol) in CH₂Cl₂ (10 mL). The reaction mixture was stirred at roomtemperature for 30 min, and was then extracted with EtOAc and washedwith water, 1 N HCl, and water again. The organic extracts were driedover MgSO₄, filtered, and concentrated. The residue was purified byflash chromatography (silica gel, 0% to 100% EtOAc in hexanes) to givecompound 2 (1.08 g, 97% from RTA 401) as an off-white foam solid: m/z548.3 (M+1).

Compound TX63384: To a solution of compound 2 (548 mg, 1.00 mmol) intoluene (20 mL) was added p-TsOH (95 mg, 0.50 mmol). The reaction washeated at 135° C. with a Dean-Stark condenser attached for 1.5 h. Aftercooling to room temperature, the reaction mixture was washed with water,dried over MgSO₄, filtered, and concentrated. The residue was purifiedby flash chromatography (silica gel, 0% to 70% EtOAc in hexanes) to givecompound TX63384 (390 mg, 74%) as an off-white foam solid: ¹H NMR (400MHz, CDCl₃) δ 8.02 (s, 1H), 5.96 (s, 1H), 3.13 (m, 1H), 2.94 (d, 1H,J=4.5 Hz), 2.53 (s, 3H), 2.19 (m, 1H), 1.20-2.05 (m, 14H), 1.45 (s, 3H),1.25 (s, 3H), 1.19 (s, 3H), 1.16 (s, 3H), 1.06 (s, 3H), 1.05 (s, 3H),0.95 (s, 3H); m/z 530.3 (M+1).

Compound 3: To a solution of butyric acid hydrazide (156 mg, 1.53 mmol)and Et₃N (0.58 mL, 4.16 mmol) in CH₂Cl₂ (5 mL) was added a solution ofcompound 1 (510 mg, 1.00 mmol) in CH₂Cl₂ (5.0 mL). The reaction mixturewas stirred at room temperature for 2.5 h. The reaction mixture was thenextracted with EtOAc and washed with 1 N HCl and brine. The organicextracts were dried over Na₂SO₄, filtered, and concentrated. The residuewas purified by flash chromatography (silica gel, 0% to 100% EtOAc inhexanes) to give compound 3 (566 mg, 98%) as a white solid: m/z 576.4(M+1).

Compound TX63475: To a solution of compound 3 (197 mg, 0.342 mmol) intoluene (12 mL) was added p-TsOH (33 mg, 0.174 mmol). The reaction washeated at 135° C. with a Dean-Stark condenser attached for 2.5 h. Aftercooling to room temperature, the reaction mixture was extracted withEtOAc and washed with saturated NaHCO₃ and brine. The organic extractswere dried over Na₂SO₄, filtered, and concentrated. The residue waspurified by flash chromatography (silica gel, 100% EtOAc in hexanes) togive compound TX63475 (159 mg, 83%) as a white solid: ¹H NMR (400 MHz,CDCl₃) δ 8.01 (s, 1H), 5.95 (s, 1H), 3.14 (td, 1H, J=4.3, 13.4 Hz), 2.94(d, 1H, J=4.7 Hz), 2.81 (t, 2H, J=7.6 Hz), 2.19 (m, 1H), 1.93 (m, 3H),1.50 (m, 13H), 1.45 (s, 3H), 1.25 (s, 3H), 1.16 (s, 3H), 1.15 (s, 3H),1.05 (s, 3H), 1.04 (s, 3H), 0.99 (t, 3H, J=7.4 Hz), 0.95 (s, 3H); m/z558.4 (M+1).

Compound 4: To a solution of isobutyric acid hydrazide (153 mg, 1.50mmol) and Et₃N (0.58 mL, 4.16 mmol) in CH₂Cl₂ (5 mL) was added asolution of compound 1 (510 mg, 1.00 mmol) in CH₂Cl₂ (5.0 mL). Thereaction mixture was stirred at room temperature for 3 h. The reactionmixture was then extracted with EtOAc and washed with 1 N HCl and brine.The organic extracts were dried over Na₂SO₄, filtered, and concentrated.The residue was purified by flash chromatography (silica gel, 0% to 100%EtOAc in hexanes) to give compound 4 (525 mg, 91%) as a white solid: m/z576.4 (M+1).

Compound TX63476: To a solution of compound 4 (282 mg, 0.490 mmol) intoluene (12 mL) was added p-TsOH (48 mg, 0.253 mmol). The reaction washeated at 135° C. with a Dean-Stark condenser attached for 1 h. Aftercooling to room temperature, the reaction mixture was extracted withEtOAc and washed with saturated NaHCO₃ and brine. The organic extractswere dried over Na₂SO₄, filtered, and concentrated. The residue waspurified by flash chromatography (silica gel, 0% to 100% EtOAc inhexanes) to give compound TX63476 (233 mg, 85%) as a white solid: ¹H NMR(400 MHz, CDCl₃) δ 8.02 (s, 1H), 5.95 (s, 1H), 3.17 (m, 2H), 2.99 (d,1H, J=4.7 Hz), 2.18 (dt, 1H, J=4.2, 14.8 Hz), 1.90 (m, 3H), 1.45 (m,11H), 1.45 (s, 3H), 1.37 (d, 6H, J=7.0 Hz), 1.25 (s, 3H), 1.16 (s, 3H),1.15 (s, 3H), 1.05 (s, 3H), 1.04 (s, 3H), 0.95 (s, 3H); m/z 558.3 (M+1).

Compound 5: To a solution of cyclopropane carboxylic acid hydrazide (155mg, 1.55 mmol) and Et₃N (0.58 mL, 4.16 mmol) in CH₂Cl₂ (5 mL) was addeda solution of compound 1 (510 mg, 1.00 mmol) in CH₂Cl₂ (5.0 mL). Thereaction mixture was stirred at room temperature for 3.5 h. The reactionmixture was then extracted with EtOAc and washed with 1 N HCl and brine.The organic extracts were dried over Na₂SO₄, filtered, and concentrated.The residue was purified by flash chromatography (silica gel, 0% to 100%EtOAc in hexanes) to give compound 5 (495 mg, 86%) as a white solid: m/z574.3 (M+1).

Compound TX63477: To a solution of compound 5 (288 mg, 0.502 mmol) intoluene (12 mL) was added p-TsOH (55 mg, 0.289 mmol). The reaction washeated at 150° C. with a Dean-Stark condenser attached for 2.5 h. Aftercooling to room temperature, the reaction mixture was extracted withEtOAc and washed with saturated NaHCO₃ and brine. The organic extractswere dried over Na₂SO₄, filtered, and concentrated. The residue waspurified by flash chromatography (silica gel, 0% to 100% EtOAc inhexanes) to give compound TX63477 (231 mg, 83%) as a white solid: ¹H NMR(400 MHz, CDCl₃) δ 8.02 (s, 1H), 5.95 (s, 1H), 3.10 (td, 1H, J=3.6, 13.2Hz), 2.98 (d, 1H, J=4.7 Hz), 2.12 (m, 2H), 1.90 (m, 3H), 1.45 (s, 3H),1.43 (s, 15H), 1.25 (s, 3H), 1.18 (s, 3H), 1.16 (s, 3H), 1.04 (s, 3H),1.04 (s, 3H), 0.94 (s, 3H); m/z 556.3 (M+1).

Compound 6: To a solution of methoxyacetic acid hydrazide (166 mg, 1.59mmol) and Et₃N (0.56 mL, 4.02 mmol) in CH₂Cl₂ (5 mL) was added asolution of compound 1 (510 mg, 1.00 mmol) in CH₂Cl₂ (5.0 mL). Thereaction mixture was stirred at room temperature for 4 h. The reactionmixture was then extracted with EtOAc and washed with 1 N HCl and brine.The organic extracts were dried over Na₂SO₄, filtered, and concentrated.The residue was purified by flash chromatography (silica gel, 0% to 100%EtOAc in hexanes) to give compound 6 (495 mg, 86%) as a white foamsolid: m/z 578.4 (M+1).

Compound TX63478: To a solution of compound 6 (292 mg, 0.505 mmol) intoluene (12 mL) was added p-TsOH (48 mg, 0.253 mmol). The reaction washeated at 150° C. with a Dean-Stark condenser attached for 1 h. Aftercooling to room temperature, the reaction mixture was extracted withEtOAc and washed with saturated NaHCO₃ and brine. The organic extractswere dried over Na₂SO₄, filtered, and concentrated. The residue waspurified by flash chromatography (silica gel, 0% to 100% EtOAc inhexanes) to give compound TX63478 (158 mg, 56%) as a white solid: ¹H NMR(400 MHz, CDCl₃) δ 8.02 (s, 1H), 5.96 (s, 1H), 4.63 (s, 2H), 3.43 (s,3H), 3.18 (td, 1H, J=4.2, 13.7 Hz), 3.01 (d, 1H, J=4.7 Hz), 2.21 (m,1H), 1.91 (m, 3H), 1.50 (m, 11H), 1.45 (s, 3H), 1.24 (s, 3H), 1.16 (s,3H), 1.15 (s, 3H), 1.05 (s, 3H), 1.05 (s, 3H), 0.95 (s, 3H); m/z 560.3(M+1).

Compound 7: To a solution of formic acid hydrazide (92 mg, 1.53 mmol)and Et₃N (0.56 mL, 4.02 mmol) in CH₂Cl₂ (5 mL) was added a solution ofcompound 1 (510 mg, 1.00 mmol) in CH₂Cl₂ (5.0 mL). The reaction mixturewas stirred at room temperature for 1.5 h. The reaction mixture was thenextracted with EtOAc and washed with 1 N HCl and brine. The organicextracts were dried over Na₂SO₄, filtered, and concentrated. The residuewas purified by flash chromatography (silica gel, 0% to 100% EtOAc inhexanes) to give compound 7 (257 mg, 48%) as a white solid: m/z 534.3(M+1).

Compound TX63479: To a solution of compound 7 (256 mg, 0.480 mmol) intoluene (12 mL) was added p-TsOH (48 mg, 0.253 mmol). The reaction washeated at 150° C. with a Dean-Stark condenser attached for 1 h. Aftercooling to room temperature, the reaction mixture was extracted withEtOAc and washed with saturated NaHCO₃ and brine. The organic extractswere dried over Na₂SO₄, filtered, and concentrated. The residue waspurified by flash chromatography (silica gel, 0% to 100% EtOAc inhexanes) to give compound TX63479 (120 mg, 49%) as a white solid: ¹H NMR(400 MHz, CDCl₃) δ 8.36 (s, 1H), 8.01 (s, 1H), 5.96 (s, 1H), 3.20 (td,1H, J=3.8, 13.3 Hz), 2.91 (d, 1H, J=4.8 Hz), 2.23 (m, 1H), 1.93 (m, 3H),1.46 (m, 11H), 1.44 (s, 3H), 1.25 (s, 3H), 1.15 (s, 3H), 1.14 (s, 3H),1.06 (s, 3H), 1.05 (s, 3H), 0.96 (s, 3H); m/z 516.3 (M+1).

Compound 8: To a solution of acetamide oxime (113 mg, 1.53 mmol) andEt₃N (0.56 mL, 4.02 mmol) in CH₂Cl₂ (5 mL) was added a solution ofcompound 1 (510 mg, 1.00 mmol) in CH₂Cl₂ (5.0 mL). The reaction mixturewas stirred at room temperature for 5 h. The reaction mixture was thenconcentrated. The residue was purified by flash chromatography (silicagel, 0% to 100% EtOAc in hexanes) to give compound 8 (510 mg, 93%) as awhite solid: m/z 548.3 (M+1).

Compound TX63501: Compound 8 (27 mg, 0.049 mmol) was dissolved intoluene (1 mL), and the solution was heated via microwave heating at170° C. for 10 min, followed by 200° C. for 20 min. After cooling toroom temperature, the reaction mixture was concentrated. The residue waspurified by flash chromatography (silica gel, 0% to 80% EtOAc inhexanes) to give compound TX63501 (12 mg, 46%) as a white solid: ¹H NMR(400 MHz, CDCl₃) δ 8.01 (s, 1H), 5.95 (s, 1H), 3.14 (m, 1H), 3.02 (d,1H, J=4.7 Hz), 2.21 (s, 3H), 2.14 (m, 1H), 1.93 (m, 3H), 1.50 (m, 13H),1.45 (s, 3H), 1.25 (s, 3H), 1.18 (m, 1H), 1.16 (s, 3H), 1.15 (s, 3H),1.04 (s, 3H), 0.98 (s, 3H); m/z 530.3 (M+1).

Compound 9: To a solution of compound TX63199 (52 mg, 0.103 mmol) inCH₂Cl₂ (2 mL) were added acetic hydrazide (18.6 mg, 0.251 mmol), Et₃N(28 μL, 0.201 mmol), and DMAP (24.4 mg, 0.200 mmol). EDCI (40 mg, 0.209mmol) was then added, and the reaction was stirred at room temperaturefor 17 h. The reaction mixture was extracted with EtOAc and washed withsaturated 1 N HCl and brine. The organic extracts were dried overNa₂SO₄, filtered, and concentrated. The residue was purified by flashchromatography (silica gel, 0% to 10% MeOH in CH₂Cl₂) to give compound 9(33 mg, 57%) as a white solid: m/z 512.3 (M+1).

Compound TX63593: To a solution of compound 9 (25 mg, 0.045 mmol) intoluene (1.5 mL) was added p-TsOH (4.8 mg, 0.025 mmol). The reactionmixture was heated via microwave heating at 125° C. for 1 h. Aftercooling to room temperature, the reaction mixture was extracted withEtOAc and washed with saturated NaHCO₃ and brine. The organic extractswere dried over Na₂SO₄, filtered, and concentrated. The residue waspurified by flash chromatography (silica gel, 20% to 100% EtOAc inhexanes) to give compound TX63593 (11 mg, 46%) as an off-white solid: ¹HNMR (400 MHz, CDCl₃) δ 8.04 (s, 1H), 6.01 (s, 1H), 3.12 (d, 1H, J=5.0Hz), 3.12 (d, 1H, J=14.1 Hz), 2.69 (d, 1H, J=14.5 Hz), 2.52 (s, 3H),2.27 (m, 1H), 1.98 (m, 2H), 1.78 (m, 3H), 1.56 (m, 3H), 1.56 (s, 3H),1.52 (s, 3H), 1.27 (s, 3H), 1.19 (m, 7H), 1.19 (s, 3H), 1.04 (s, 3H),0.91 (s, 3H), 0.88 (s, 3H); m/z 544.3 (M+1).

All of the compounds, compositions and methods disclosed and claimedherein can be made and executed without undue experimentation in lightof the present disclosure. While the disclosure may have only beendescribed in terms of certain embodiments, it will be apparent to thoseof skill in the art that variations may be applied to the compounds,compositions and methods and in the steps or in the sequence of steps ofthe method described herein without departing from the concept, spiritand scope of the invention. More specifically, it will be apparent thatcertain agents which are both chemically and physiologically related maybe substituted for the agents described herein while the same or similarresults would be achieved. All such similar substitutes andmodifications apparent to those skilled in the art are deemed to bewithin the spirit, scope and concept of the invention as defined by theappended claims.

REFERENCES

The following references to the extent that they provide exemplaryprocedural or other details supplementary to those set forth herein, arespecifically incorporated herein by reference.

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What is claimed is:
 1. A compound of the formula:

wherein: n is 0 or 1; Ar is

 and Y is: hydrogen, alkyl_((C≤8)), or substituted alkyl_((C≤8)); or apharmaceutically acceptable salt thereof.
 2. The compound of claim 1,further defined as:

or a pharmaceutically acceptable salt thereof.
 3. The compound of claim1, further defined as:

or a pharmaceutically acceptable salt thereof.
 4. The compound of claim1, further defined as:

or a pharmaceutically acceptable salt thereof.
 5. The compound of claim1, further defined as:

or a pharmaceutically acceptable salt thereof.
 6. The compound of claim1, further defined as:

or a pharmaceutically acceptable salt thereof.
 7. The compound of claim1, further defined as:

or a pharmaceutically acceptable salt thereof.
 8. The compound of claim1, further defined as:

or a pharmaceutically acceptable salt thereof.
 9. The compound of claim1, further defined as:

or a pharmaceutically acceptable salt thereof.
 10. A pharmaceuticalcomposition comprising: a) the compound of claim 1; and b) an excipient.